85% of sporadic hyperparathyroidism cases have a solitary adenoma. The remaining 15% of cases have multiple tumors. About 95% of all cases achieve a long remission at initial operation. Adverse outcomes are increased in multigland disease and in cases with prior failed operation; the adverse outcomes include damage to important structures such as the recurrent laryngeal nerve(s), hypoparathyroidism, persistent hyperparathyroidism, and late recurrent hyperparathyroidism. Approximately half of new referrals to NIH have had prior failed neck exploration for hyperparathyroidism; they have been referred because of our expertise for these cases. The surgical success rate at NIH in these difficult cases has been 95%. This group is enriched for multi gland hyperparathyroidism and thus for hereditary causes. We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We find germline mutations in 70-80% of probands with familial MEN1 or at lower prevalence in cases with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have rare (about 5%) MEN1 mutations. Among the MEN1-like families without MEN1 mutation, a rare family shows mutation of the p27 cylclin dependent kinase inhibitor (CDKI) gene. p27 germline mutation in MEN1 is about 1% the frequency of MEN1 mutation. We have also found rare germline mutation of p15, p18, or p21 CDKIs. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Thus MEN1 is the gene most frequently implicated in common endocrine tumors. We found p18 CDKI in a sporadic parathyroid adenoma. We will also determine the spectrum of pathologic states that the MEN1 or the CDKI genes contribute to through mutation and other mechanisms. The cause of solitary (non-familial) parathyroid adenoma is believed to be somatic mutation of some gene, with overgrowth of a tumor clone. Mutation of the cyclin D1 (PRAD1) gene accounts for about 3-4%. Sporadic (nonhereditary) mutation of the MEN1 gene is the most common known mutation, causing 25-30% of solitary and common variety adenomas. The ZFX gene is mutated in 6%. Of the 15% of cases with multigland disease, 5% (1/3 of 15%) have a familial form. 4% of the 5% have familial MEN1 or familial hypocalciuric hypercalcemia. About 1% have familial isolated hyperparathyroidism (FIHP). The underlying gene for FIHP is GCM2 (gain-of-function mutation) in approximately 20% of cases. The underlying gene(s)for the remaining 80% of FIHP are not known. Among all MEN1-like cases without identified mutation, 3.5% have mutation in a cyclin dependent kinase inhibitor gene, specifically p15, p18, p21, or p27.